Complement Mediated Neovascularization in Retinopathy

病理性新生血管形成是早产儿视网膜病变（ROP）的标志 和糖尿病性视网膜病变（DR），其中新血管形成和 退化决定疾病的严重程度。该提案研究了一种新的机制 由此病理性新血管被靶向用于消退，同时保留了 需要正常的血管床视网膜病变是一种由血管起始的两阶段性疾病 损失由此产生的缺氧导致病理反应，新血管形成， 如果不加以控制，会导致失明。最佳治疗可以消除 新生血管生长，同时保留组织必需的正常血管 体内平衡在这种情况下，一种有吸引力的方法认为先天免疫，介导 部分是由补体系统引起的。到目前为止， 对增殖性视网膜病了解甚少。在这里，我们将描述的作用， 补体系统在病理性新生血管形成和清除中的作用 氧诱导视网膜病变（OIR）的小鼠模型。我们将决定 经典的，替代的和凝集素补体途径和内源性膜- 血管脱落、损伤后血管再生、新生血管中的结合补体抑制剂 在OIR进展期间的发展和新血管消退。我们将使用击倒 缺乏每种补体途径的小鼠和仅含有一种功能性补体途径的小鼠 补体途径 初步数据表明，补体系统起着重要的作用， 在消除新生血管同时保留正常脉管系统中的作用。补体因子-B， 一种替代补体级联的激活剂，在视网膜中显著增加， 并局限于新生血管。缺乏补体因子的小鼠- B显示新血管形成的严重程度和持续时间增加。CD 55，补体 保护健康宿主细胞免受补体相关破坏的抑制剂， 仅与正常脉管系统相关而不与新生血管相关。这些数据表明 替代补体级联在介导清除 视网膜中的病理性新生血管。然而，其他人的贡献 该过程中的补体途径仍然未知。了解机制 补体系统介导的新血管清除可能会打开新的 ROP和其他致盲性新生血管性眼科疾病的治疗途径。

Pathological neovascularization is a hallmark of retinopathy of prematurity (ROP) and diabetic retinopathy (DR), where the balance between neovessel formation and regression determines disease severity. This proposal investigates a novel mechanism whereby pathological neovessels are targeted for regression while preserving the required normal vascular bed. Retinopathy is a two-phased disease initiated by vessel loss. The resulting hypoxia drives a pathologic response, neovascularization, which when unchecked can progress to blindness. Optimal therapy would eliminate neovascular growth while sparing normal vessels that are essential to tissue homeostasis. An attractive approach in this context considers innate immunity, mediated in part by the complement system. To date, the contribution of complement in proliferative retinopathy is poorly understood. Here we will characterize the role of the complement system in the formation and clearance of pathological neovessels in a mouse model of oxygen-induced retinopathy (OIR). We will determine the contribution of the classical, alternative and lectin complement pathways and endogenous membrane- bound complement inhibitors in vascular dropout, vessel regrowth after injury, neovessel development and neovessel regression during OIR progression. We will utilize knockout mice lacking each complement pathway and in mice containing only one functional complement pathway. Preliminary data demonstrates that the complement system plays an important role in eliminating neovessels while sparing normal vasculature. Complement factor-B, an activator of the alternative complement cascade, is significantly increased in retinas with neovascularization and is localized to neovessels. Mice lacking complement factor- B show increased severity and duration of neovascularization. Cd55, a complement inhibitor that protects healthy host cells from complement-associated destruction, is associated only with the normal vasculature and not neovessels. These data indicate that the alternative complement cascade is important in mediating the clearance of pathological neovessels in the retina. However the contributions of the other complement pathways in this process remain unknown. Understanding the mechanism by which the complement system mediates neovessel clearance may open new avenues of therapy for ROP and other blinding neovascular ophthalmic diseases.